2-Chlorodeoxyadenosine inhibits the repair of DNA double-strand breaks and does not inhibit the repair of DNA single-strand breaks in X-irradiated Chinese hamster V79 cells

The action of hydrogen atoms — generated in an electrodeless high frequency gas discharge — on calf thymus DNA in aqueous solution was investigated. The loss of priming activity was compared with the appearance of single strand breaks in native and denatured DNA, double strand breaks, denatured zones, base damage and rupture of hydrogen bonds. The primary lesions after exposure to H atoms and gamma radiation, respectively, are single strand breaks and base damage. Double strand breaks originating from accumulation of single breaks, and rupture of hydrogen bonds caused by single breaks and base damage, were identified as secondary lesions. In relation to strand breaks arising from radical attack on the sugar-phosphate backbone of the DNA molecule, base damage is about 12.5 times more frequent after Η-exposure than after γ-irradiation. It is concluded from this observation, that single strand breaks are the predominant critical lesions responsible for the loss of the functional activity of DNA.

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The oxygen effect in permeabilized and histone-depleted cells: An enhanced OER for DNA double-strand breaks, compared to single-strand breaks, is abolished by soluble scavengers

International Journal of Radiation Biology ◽

10.1080/095530097143383 ◽

1997 ◽

Vol 72 (2) ◽

pp. 163-170 ◽

Cited By ~ 9

Author(s):

J. NYGREN and G. AHNSTROM

Keyword(s):

Double Strand Breaks ◽

Single Strand ◽

Oxygen Effect ◽

Dna Double Strand Breaks ◽

Strand Breaks ◽

Single Strand Breaks

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Delayed repletion of O6-methylguanine—DNA methyltransferase resulting in failure to protect the human glioblastoma cell line SF767 from temozolomide-induced cytotoxicity

Journal of Neurosurgery ◽

10.3171/jns.2003.98.3.0591 ◽

2003 ◽

Vol 98 (3) ◽

pp. 591-598 ◽

Cited By ~ 24

Author(s):

Yuichi Hirose ◽

Emiko L. Kreklau ◽

Leonard C. Erickson ◽

Mitchel S. Berger ◽

Russell O. Pieper

Keyword(s):

Cell Death ◽

Dna Methyltransferase ◽

Glioma Cells ◽

Double Strand Breaks ◽

Single Strand ◽

Dna Double Strand Breaks ◽

Content Type ◽

Strand Breaks ◽

Single Strand Breaks ◽

Fine Print

Object. Temozolomide (TMZ)-induced O6-methylguanine (MG) DNA lesions, if not removed by MG—DNA methyltransferase (MGMT), mispair with thymine, trigger rounds of futile mismatch repair (MMR), and in glioma cells lead to prolonged G2—M arrest and ultimately cell death. Depletion of MGMT by O6-benzylguanine (BG) sensitizes tumor cells to TMZ, and this combination is currently used in clinical trials. The use of the TMZ+BG combination in gliomas, however, is complicated by the prolonged TMZ-induced G2—M arrest, which may delay activation of poorly defined cell death pathways and allow for MGMT repletion and reversal of toxicity. Methods. To address these issues, the actions of TMZ were monitored in DNA MMR-proficient SF767 glioma cells depleted of MGMT by BG, and in cells in which BG was removed at various times after TMZ exposure. In MGMT-depleted cells, TMZ exposure led to DNA single-strand breaks and phosphorylation of cdc2, followed by G2—M arrest, induction of p53/p21, and DNA double-strand breaks. Although DNA single-strand breaks, phosphorylation of cdc2, and G2—M arrest could be reversed by repletion of MGMT up to 5 days after TMZ exposure, TMZ-induced cytotoxicity could only be prevented if MGMT was replenished within 24 hours of the onset of G2—M arrest, and before the creation of DNA double-strand breaks. Conclusions. These results indicate that although SF767 glioma cells undergo a prolonged G2—M arrest in response to TMZ, their ability to escape TMZ-induced cytotoxicity by MGMT repletion is limited to an approximately 24-hour period after the onset of G2—M arrest.

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